The present invention relates to the discovery, identification and characterization of a novel tumor suppressor gene PARIS-1 (“Prostate Antigen Recognized and Identified by SEREX”-1). The invention encompasses nucleotide sequences of the PARIS-1 gene and amino acid sequences of its encoded protein product(s), as well as derivatives and analogs thereof. The invention also encompasses the production of PARIS-1 proteins and antigen specific antibodies. The invention further encompasses compositions and methods for diagnostic and therapeutic applications for prostate cancer.
Prostate cancer is the most commonly diagnosed cancer in men in the United States and around the world. It accounts for 29% of all cancers in men in the United States and is one of the most frequent causes of cancer death in men throughout the world. This year, approximate 179,300 new cases of prostate cancer are expected to be diagnosed and approximately 37,000 will succumb to their disease (Landis et al., CA Cancer J Clin. 49:8–31 (1999)). Still, the number of cases of prostate cancer in the year 2000 and beyond are expected to increase (Boyle, In, First International Consultation on Prostate Cancer, Monaco, Jun. 20–Jun. 22 1996, pp. 1–30). Thus, prostate cancer will remain as a serious public health concern in the United States and around the world.
Tumor suppressor genes play an important role in normal cell growth, differentiation and progression through the cell cycle. Tumor suppressor genes in humans have been identified through studies of genetic changes in occurring in cancer cells (Ponder, Trends Genet. 6:213–218 (1990); Weinberg, Science 254:1138–1146 (1991)). Mutations that cause change in gene expression of tumor suppressor genes lead to cell transformation in vitro and tumor development in vivo. It has been documented that loss of tumor suppressor(s) genes at chromosome 10, chromosome 8, chromosome 13, or mutations in p53 could be events leading to prostate cancer (Arbieva et al., Genome Res. 10:244–257 (2000); Yin et al., Oncogene 18:7576–7583 (1999); Zou et al., J. Biol. Chem. 275:6051–6054 (2000)). The exact series of events involving tumor suppressor genes that lead to initiation and progression of cancer is not known.
Prostate cancer is a slow growing disease and possesses a multiple-step nature during the process of its carcinogenesis. It usually starts as a localized benign disease, then advances gradually into metastasis, and eventually develops into a hormone resistant cancer (Small, Curr. Opin. Oncol. 9:277–286 (1997); Weber, Semin. Oncol. Nurs., 13:99–107 (1997); Carducci, et al., Semin. Oncol. 23:56–62 (1996); Royai, et al., Semin. Oncol. 23:35–40 (1996)). The progression of the cancer is accompanied by a series of morphological, histological and pathological changes. A number of genetic alterations have also been observed during the progression of prostate cancer, as described above and further inactivation of tumor suppressor genes, such as p53, Rbl, PTEN, DCC, and KAI, mutation of oncogenes such as Ras, loss of heterozygosity on certain chromosome loci such chromosome 8p, 10q, 16q, 17p, and 18q, and suppression of certain gene expression such as E-cadherin/a-catenin (Small, supra; Weber, supra; Carducci et al., supra; Isaacs, Cancer Surv. 25:357–379 (1995); Isaacs, et al., Semin. Oncol. 21:514–521 (1994); Hrouda, et al., Gene Ther. 3:845–852 (1996); Nupponen, et al., Cancer Genet. Cytogenet. 101:53–57 (1998)).
The search for tumor-specific or -associated antigens that induce specific immune responses in cancer patients remains a challenge in tumor immunology. Significant efforts have been made during the past decades in developing efficient strategies for identification of tumor-specific and -associated antigens, and a number of strategies including both immunological and non-immunological strategies have been developed and used for tumor-specific and -associated antigen identification. The immunological approaches most commonly used include: (1) a genetic approach based on the recognition of expressed tumor-specific or -associated antigens by autologous tumor-specific cytotoxic T lymphocyte CTL clones (van der Bruggen, et al., Science 254:1643–1647 (1991)); (2) a biochemical approach based on the acid elution of antigenic peptide bound to Major Histocompatibility Complex (MHC) class I molecules from tumor cells (Mandelboim, et al., Nature 369:67–71 (1994), (published erratum appears in Nature 390:643 (1997)); Falk, et al., Nature 351:290–296 (1991); Van Bleek, et al., Nature 348:213–216 (1990)); and (3) a serological approach, also known as autologous typing, based on the use of autologous serum to detect cell-surface antigens on the tumor cells of cancer patients (Pfreundschuh, et al., Proc. Natl. Acad. Sci. USA 75:5122–5126 (1978); Shiku, et al., J. Exp. Med. 144.873–881 (1976); Ueda, et al., J. Exp. Med. 150:564–579 (1979).
Using such approaches, a number of human tumor antigens have been identified from several tumor types (Van der Bruggan, supra; Mandeboim, supra; Falk, supra; Van Bleek and Nathenson, supra; Boel, et al., Immunity 2:167–175 (1995); Brichard, et al., J. Exp. Med. 178:489–495 (1993); Coulie, et al., J. Exp. Med. 180:35–42 (1994); Kawakami, et al., Proc. Natl. Acad. Sci. USA 91:6458–6462 (1994); Kawakami, et al., Proc. Natl. Acad. Sci. USA. 91:3515–3519 (1994); Xue, et al., Prostate 30:73–78 (1997)). Both animal tumor models and human clinical trials have been developed to evaluate the identified tumor antigens in prevention and treatment of a variety of cancers. T cell responses have been detected, and some clinical benefits observed for some of the antigens. (Salgaller, et al., Cancer Res. 56:4749–4757 (1996); Hsu, et al., Nat. Med. 2:52–58 (1996); Borysiewicz, et al., Lancet 347:1523–1527 (1996); McAneny, et al., Ann. Surg. Oncol. 3:495–500 (1996); Cormier, et al., Cancer J. Sci. Am. 3:37–44 (1997); Pass, et al., Cancer J. Sci. Am. 4:316–323 (1998); Reynolds, et al., J. Immunol. 161:6970–6976 (1998); Rosenberg, et al., Nat. Med. 4:321–327 (1998); Rosenberg, et al., J. Natl. Cancer Inst. 90: 1894–1900 (1998); Spagnoli, et al., Int. J. Cancer 64:309–315 (1995); Kim, et al., J. Immunother. 20:276–286 (1997); Nestle, et al., Nat. Med. 4:328–332 (1998); Song, et al., J. Exp. Med. 186:1247–1256 (1997)).
However, all these approaches have encountered limitations in their further application and expansion to a broader range of tumor types. For example, defining T cell-recognized tumor antigens often depended on the pre-establishment of stable CTL clones that are often difficult to establish. Using autologous cell lines limits analysis to tumor cells that could be adapted to growth in vitro with some regularity such as melanoma (Shiku, supra; Carey, et al., Proc. Natl. Acad. Sci. USA 73:3278–282 (1976)), renal cancer (Ueda, supra), and brain cancer (Pfrunschuh, supra). Non-immunological strategies, including recently developed approaches such as differential display, subtractive cloning/hybridization, DNA microarray, are based solely on the differential expression of genes between tumor cells and their normal counterparts, or purely on computer analysis of the GenBank database such as database mining. The gene products identified by these approaches may be used as markers for diagnosis. However, their candidacy for use in immunotherapy remains unknown because no information on their antigenicity and immunogenicity is obtained by using these approaches.
Serological identification of antigens by Recombinant Expression cloning (SEREX) has emerged in recent years as a novel approach for identifying tumor antigens (Sahin, et al., Proc. Natl. Acad. Sci. USA 92:11810–11813 (1995)). This approach utilizes autologous patient sera to search for tumor antigens expressed in bacteria Escherichia coli, which are infected with lambda phages containing cDNA libraries prepared from fresh tumor tissues. Thus, this new approach bypasses both requirements for the pre-establishments of stable cytotoxic T lymphocyte (CTL) clones or tumor-infiltrating lymphocytes (TIL), and established tumor cell lines. The use of SEREX technology in identification of human tumor antigens has been successful in a number of tumor types, including melanoma (Sahin, supra; Tureci, et al., Cancer Res. 56:4766–4772 (1996)), renal cancer (Sahin, supra; Tureci, et al., Mol. Med. Today 3:342–349 (1997), astrocytoma (Sahin, supra), Hodgkin's disease (Sahin, supra; Tureci, et al., J. Biol. Chem. 272:6416–6422 (1997)), esophageal cancer (Sahin, supra), lung cancer (Brass, et al., Hum. Mol. Genet. 6:33–39 (1997); Gure, et al., Cancer Res. 58:1034–1041 (1998)), and colon cancer (Scanlan, et al., Int. J. Cancer 76:652–658 (1998), and a number of tumor specific or associated antigens have been identified from these cancers.
The tumor antigens identified by SEREX are immunogenic and are good candidates for agents in the treatment of cancer, including vaccines, when the cognate T cell epitopes are discerned. The ability of a SEREX-identified antigen to be recognized by CTLs has been demonstrated in a recent study showing that the peptide epitopes derived from a SEREX-identified tumor antigen NY-ESO-1 were recognized by CTLs from a patient with high NY-ESO-1 antibody titers (Jager, et al., J. Exp. Med. 187:265–270 (1998)). Moreover, some of the SEREX-identified tumor antigens such as MAGE-1, MAGE-3, MAGE-4 and tyrosinase had also been previously identified by the CTL approach (Brichard, supra; Gaugler, et al., J. Exp. Med. 179:921–930 (1994); De Plaen, et al., Immunogenetics 40:360–369 (1994)).
Prostate tumor antigens identified recently by using molecular approaches such as differential display or subtractive cloning include prostatic carcinoma oncogene PTI-1 (Shen, et al., Proc. Natl. Acad. Sci. USA 92:6778–6782 (1995); Sun, et al., Cancer Res. 57:18–23 (1997)), prostate carcinoma tumor antigen PCTA-1 (Su, et al., Proc. Natl. Acad. Sci. USA 93:7252–7257 (1996)); NPC-1 (Yang, et al., Cancer Res. 58:3732–3735 (1998)); PAGE-1 and GAGE-7 (Brinklmann, et al., Proc. Natl. Acad. Sci. USA 95:10757–10762 (1998); Chen, et al., J. Biol. Chem. 273:17618–17625 (1998)). Some of these antigens displayed a pattern of restricted expression in prostate or prostate cancer cells, but it is crucial to point out that none have been shown to induce either cellular or humoral immune responses. Thus, the possibility of using these antigens for the specific immunotherapy of prostate cancer remains unclear. Therefore, there continues to exist a need for identifying additional antigens associated with prostate tissue or tumor antigens that are useful as agents to treat hyperplastic and malignant conditions that are either immunogenic and capable of acting as tumor-rejection antigens or that function to suppress tumor development in prostate cancer patients.